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Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified  PIK3CA  mutant ( PIK3CA  MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in  PIK3CA  wild type ( PIK3CA  WT) cell lines, while  PIK3CA  MT cells did not respond to SMI-4a in cell death assays.  In vivo  xenograft and PDX experiments confirmed that  PIK3CA  MT is responsible for the resistance to SMI-4a. Inhibition of  PIK3CA  MT by PI3K inhibitors restored SMI-4a sensitivity in  PIK3CA  MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the  PIK3CA  genotype and that co-targeting of PI3K and PIM1 in  PIK3CA  MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.

Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer